A principal function of the gastrointestinal tract is to process and absorb food. The stomach, which is both a storage and digestive organ, works to optimize the conditions for the digestion and absorption of food in the small intestine. Following the stomach and preceding the large bowel (colon) is the small intestine, which comprises three regions: the duodenum, jejunum, and ileum. A major function of the small intestine is one of absorption of digested nutrients.
The passage of a meal through the gastrointestinal tract, which leads to digestion and absorption of nutrients, is controlled by a complex system of inhibitory and stimulatory motility mechanisms which are set in motion by the composition of the meal ingested. Specific receptors for fats and proteins, and the osmolality, acidity and particle size of the meal activate propulsive and inhibitory reactions, which modulate transit and thus absorption. In normal human subjects, the mechanisms that regulate gastrointestinal transit can, under some circumstances, be sensitized or desensitized in response to the subject's recent dietary history. (Cunningham, K. M., et al., “Gastrointestinal Adaptation to Diets of Differing Fat Composition in Human Volunteers,” Gut 32(5):483-86, 1991).
The small intestine is also an important site for the absorption of pharmacological agents. The proximal part of the small intestine has the greatest capacity for absorption of drugs. Intestinal absorption of drugs is influenced to a great extent by many of the same basic factors that affect the digestion and absorption of nutrients, water and electrolytes.
Absorption of a drug in the gastrointestinal tract is a function of characteristics of the drug, such as its molecular structure, as well as attributes of the gastrointestinal tract. The rate of absorption of certain drugs, which are absorbed slowly and usually incompletely, varies according to the small intestinal transit time. Intestinal transit is important in the design of pharmaceutical preparations, especially when the absorption site of a drug is located in a particular segment of the gastrointestinal tract.
Many drugs and dosage formulations have been and continue to be developed because of the need to overcome the physiological and physicochemical limitations associated with drug delivery such as poor stability, short biological half-life, inefficient absorption and poor bioavailability. Applications of controlled release technology have moved towards control of absorption via regulation of the input to the gastrointestinal tract. However, recent pharmaceutical attempts to alter gastric emptying and small intestinal transit times have not been very successful. (Khosla and Davis, J. Pharm. Pharmacol. 39:47-49, 1987; Davis, et al., Pharm. Res. 3:208-213, 1986).
For drug absorption to proceed efficiently, the drug must first arrive at a normal absorbing surface in a form suitable for absorption; it must remain there long enough in a form and in a concentration that enhance absorption; and it must be absorbed by a normal epithelial cell without being metabolized by that cell. Accordingly, considerable advantage would be obtained if a pharmaceutical dosage form could be retained for a longer period of time within the stomach and/or the small intestine for proper absorption to occur.
The period of time during which nutrients and/or drugs are in contact with the mucosa of the small intestine is crucial for the efficacy of digestion and absorption. Inadequate residence time can lead to fecal loss of nutrients and diarrhea. Therefore, modulation of the motility rate and transit time of nutrients and/or drugs through the gastrointestinal tract will ensure optimal utilization of the absorptive surface, as well as prevent transport mechanisms from being overloaded (which could occur if substrates were passed on too rapidly and exceeded the absorptive capacity of already maximally loaded surfaces in the small intestine).
The rate of transit through the small intestine is of great significance for the rate and extent of absorption from the small intestine. Disruption of the normal digestive and absorptive processes frequently manifests as a variety of syndromes, such as, malnutrition, weight loss, diarrhea, steatorrhea, vitamin deficiency, electrolyte imbalance, and the like. Chronic diarrhea is a common problem found in a variety of gastrointestinal disorders where water, solutes and nutrients are malabsorbed (Read, N. W., “Diarrhea Motrice,” Clin. Gastroenterol. 15:657-86, 1986). Specifically, conditions such as short bowel syndrome, postgastrectomy dumping and ileal resection can lead to symptoms such as postprandial distension, cramping, abdominal pain, gaseousness, nausea, palpitations, flushing, steatorrhea or weight loss. These symptoms can persist despite the use of anti-diarrheal medications, anticholinergic agents (Ivey, K. J., “Are Anticholinergics of Use in the Irritable Bowel Syndrome?”, Gastroenterology 68:1300-07, 1975), somatostatin analogues (Reasbeck, P. G., and A. M. Van Rij, “The Effect of Somatostatin on Dumping After Surgery: A Preliminary Report,” Surgery 99:462-468, 1986), conjugated bile acid replacement therapy (Gruy-Kapral C., et al. “Conjugated Bile Acid Replacement Therapy for Short-Bowel Syndrome,” Gastroenterol. 116:15-21, 1999), or large quantities of opiates (O'Brien, J. D., et al., “Effect of Codeine and Loperamide on Upper Intestinal Transit and Absorption in Normal Subjects and Patients With Postvagotomy Diarrhea,” Gut 19:312-18, 1988). Additionally, even with treatment, fecal loss of water, solutes and nutrients can still be so excessive in some patients that long term use of parenteral fluids and nutrition can be required for survival (Rombeau, J. L., and R. H. Rolandelli, “Enteral and Parenteral Nutrition in Patients With Enteric Fistulas and Short Bowel Syndrome,” Surg. Clin. North Am. 67:551-571, 1989).
Abnormally slow gastrointestinal transit time can also have painful and serious consequences. Opioids (e.g., morphine), used for short-term or long-term pain management, commonly causes a slowing of gastrointestinal transit that can lead to bowel obstruction (ileus) or constipation. (E.g., Murthy, B. V., et al., “Intestinal Pseudo-Obstruction Associated With Oral Morphine,” Eur. J. Anaesthesiol. 15(3):370-71, 1998). Chronic constipation can result in complications including hemorrhoids, anal fissure, rectal prolapse, stercoral ulcer, melanosis coli, fecal impaction, fecal incontinence, ischemic colitis, colonic volvulus, colonic perforation, encopresis, and urinary retention. Delayed transit can also be a manifestation of a motility disorder such as idiopathic chronic intestinal pseudo-obstruction.
The speed of transit through the small intestine is normally regulated by inhibitory mechanisms located in the proximal and distal small intestine known as the jejunal brake and the ileal brake. Inhibitory feedback is activated to slow transit when end products of digestion make contact with nutrient sensors of the small intestine. (E.g., Lin, H. C., U.S. Pat. No. 5,977,175; Dobson, C. L., et al., “The Effect of Oleic Acid on the Human Ileal Brake and its Implications for Small Intestinal Transit of Tablet Formulations,” Pharm. Res. 16(1):92-96, 1999; Lin, H. C., et al., “Intestinal Transit is More Potently Inhibited by Fat in the Distal (Ileal Brake) Than in the Proximal (Jejunal Brake) Gut,” Dig. Dis. Sci. 42(1):19-25, 1997; Lin, H. C., et al., “Jejunal Brake: Inhibition of Intestinal Transit by Fat in the Proximal Small Intestine,” Dig. Dis. Sci. 41(2):326-29, 1996a).
Specifically, jejunal and ileal brakes slow transit by the release of gut peptides such as peptide YY and by the activation of neural pathways such as those involving endogenous opioids. (Lin, H. C., et al., “Fat-Induced Ileal Brake in the Dog Depends on Peptide YY,” Gastroenterol. 110(5):1491-95, 1996b). Transit is then slowed by the stimulation of nonpropagative intestinal contractions which inhibit movement of the lumenal content. The removal or impairment of these inhibitory mechanisms can lead to abnormally rapid transit. For example, in patients with a history of resection of the terminal ileum, intestinal transit can become uncontrolled and abnormally accelerated when the ileal brake is no longer intact. Time for processing of food can then be so reduced that few end products of digestion are available to trigger the jejunal brake as the remaining inhibitory mechanism.
Peptide YY and its analogs or agonists have been used to manipulate endocrine regulation of cell proliferation, nutrient transport, and intestinal water and electrolyte secretion. (E.g., Balasubramaniam, Analogs of Peptide YY and Uses Thereof, U.S. Pat. No. 5,604,203; WO9820885A1; EP692971A1; Croom, et al., Method of Enhancing Nutrient Uptake, U.S. Pat. No. 5,912,227; Litvak, D. A., et al., “Characterization of Two Novel Proabsorptive Peptide YY Analogs, BIM-43073D and BIM-43004C,” Dig. Dis. Sci. 44(3):643-48 [1999]). A role for peptide YY in the regulation of intestinal motility, secretion, and blood flow has also been suggested, as well as its use in a treatment of malabsorptive disorders (Liu, C. D., et al, “Peptide YY: A Potential Proabsorbtive Hormone for the Treatment of Malabsorptive Disorders,” Am. Surg. 62(3):232-36 [1996]; Liu, C. D., et al., “Intraluminal Peptide YY Induces Colonic Absorption in Vivo,” Dis. Colon Rectum 40(4):478-82, 1997; Bilchik, A. J., et al., “Peptide YY Augments Postprandial Small Intestinal Absorption in the Conscious Dog,” Am. J. Surg. 167(6):570-74, 1994).
Lin et al. immuno-neutralized peptide YY in vivo to block the ileal brake response and, thus, showed that it is mediated by peptide YY. (Lin, H. C., et al., “Fat-Induced Ileal Brake in the Dog Depends on Peptide YY,” Gastroenterology 110(5):1491-95, 1996b). Serum levels of peptide YY increase during the ileal brake response to nutrient infusion into the distal ileum. (Spiller, R. C., et al., “Further Characterisation of the ‘Ileal Brake’ Reflex in Man—Effect of Ileal Infusion of Partial Digests of Fat, Protein, and Starch on Jejunal Motility and Release of Neurotensin, Enteroglucagon, and Peptide YY,” Gut 29(8):1042-51, 1988; Pironi, L., et al., “Fat-Induced Ileal Brake in Humans: A Dose-Dependent Phenomenon Correlated to the Plasma Levels of Peptide YY,” Gastroenterology 105(3):733-9, 1993; Dreznik, Z., et al., “Effect of Ileal Oleate on Interdigestive Intestinal Motility of the Dog,” Dig. Dis. Sci. 39(7): 1511-8, 1994; Lin, C. D., et al., “Interluminal Peptide YY Induces Colonic Absorption in Vivo,” Dis. Colon Rectum 40(4):478-82, April 1997). In contrast, in vitro studies have shown peptide YY infused into isolated canine ileum dose-dependently increased phasic circular muscle activity. (Fox-Threlkeld, J. A., et al., “Peptide YY Stimulates Circular Muscle Contractions of the Isolated Perfused Canine Ileum by Inhibiting Nitric Oxide Release and Enchancing Acetylcholine Release,” Peptides 14(6):1171-78, 1993).
Kreutter et al. taught the use of β3-adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, as well as depression, prostate disease and dyslipidemia (U.S. Pat. No. 5,627,200).
Bagnol et al. reported the comparative immunovisualization of mu and kappa opioid receptors in the various cell layers of the rat gastrointestinal tract, including a comparatively large number of kappa opioid receptors in the myenteric plexus (Bagnol, D., et al., “Cellular Localization and Distribution of the Cloned mu and kappa Opioid Receptors in Rat Gastrointestinal Tract,” Neuroscience 81(2):579-91, 1997). They suggested that opioid receptors can directly influence neuronal activity in the gastrointestinal tract.
Kreek, et al., taught the use of opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, for the relief of gastrointestinal dysmotility. (Kreek, et al., “Method for Controlling Gastrointestinal Dysmotility,” U.S. Pat. No. 4,987,136). Riviere, et al., taught the use of the opioid receptor antagonist fedotozine in the treatment of intestinal obstructions (Riviere, P. J. M., et al., U.S. Pat. No. 5,362,756). Opioid-related constipation, the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer or participants in methadone maintenance, has been treated with orally administered methylnaltrexone and naloxone. (Yuan, C. S., et al., “Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use: Arandomized Controlled Trial,” JAMA 283(3):367-72, 2000; Meissner, W., et al., “Oral Naloxone Reverses Opioid-Associated Constipation,” Pain 84(1): 105-9, 2000; Culpepper-Morgan, J. A., et al., “Treatment of Opioid-Induced Constipation With Oral Naloxone: A Pilot Study,” Clin. Pharmacol. Ther. 52(1):90-95, 1992; Yuan, C. S., et al., “The Safety and Efficacy of Oral Methylnaltrexone in Preventing Morphine-Induced Delay in Oral-Cecal Transit Time,” Clin. Pharmacol. Ther. 61(4):467-75, 1997; Santos, F. A., et al., “Quinine-Induced Inhibition of Gastrointestinal Transit in Mice: Possible Involvement of Endogenous Opioids,” Eur. J. Pharmacol. 364(2-3):193-97, 1999. Naloxone was also reported to abolish the ileal brake in rats (Brown, N. J., et al., “The Effect of an Opiate Receptor Antagonist on the Ileal Brake Mechanism in the Rat,” Pharmacology 47(4):230-36, 1993).
Receptors for 5-Hydroxytryptamine (5-HT), also known as serotonin, have been localized on various cells of the gastrointestinal tract. (Gershon, M. D., “Review Article: Roles Played by 5-Hydroxytryptamine in the Physiology of the Bowel,” Aliment. Pharmacol. Ther. 13 Suppl 2:15-30, 1999; Kirchgessner, A. L., et al., “Identification of Cells That Express 5-Hydroxytryptamine1A Receptors in the Nervous Systems of the Bowel and Pancreas,” J. Comp. Neurol. 15:364(3):439-455, 1996). Brown, et al., reported that subcutaneous administration of 5-HT3 receptor antagonists, granisetron and ondansetron, in rats delayed intestinal transit of a baked bean meal but abolished the ileal brake induced by ileal infusion of lipid. They postulated the presence of 5-HT3 receptors on afferent nerves that initiate reflexes that both accelerate and delay intestinal transit. (Brown, N. J., et al., “Granisetron and Ondansetron: Effects on the Ileal Brake Mechanism in the Rat,” J. Pharm. Pharmacol. 45(6):521-24, 1993). Kuemmerle et al. reported neuro-endocrine 5-HT-mediation of motilin-induced accelerated gastrointestinal motility. (Kuemmerle, J. F., et al., “Serotonin Neural Receptors Mediate Motilin-Induced Motility in Isolated, Vascularly Perfused Canine Jejunum,” J. Surg. Res. 45(4):357-62, 1988).
5-HT is a mediator for the so-called “peristaltic reflex” in the mammalian colon, which mediates colonic evacuation. (E.g., Grider, J. R., et al., “5-Hydroxytryptamine4 Receptor Agonists Initiate the Peristaltic Reflex in Human, Rat, and Guinea Pig Intestine,” Gastroenterology 115(2):370-80, 1998; Jin, J. G., et al., “Propulsion in Guinea Pig Colon Induced by 5-Hydroxytryptamine (HT) Via 5-HT4 and 5-HT3 Receptors,” J. Pharmacol. Exp. Ther. 288(1):93-97, 1999; Foxx-Orenstein, A. E., et al., “5-HT4 Receptor Agonists and Delta-Opioid Receptor Antagonists Act Synergistically to Stimulate Colonic Propulsion,” Am. J. Physiol. 275(5 Pt. 1):G979-83, 1998; Foxx-Orenstein, A. E., “Distinct 5-HT Receptors Mediate the Peristaltic Reflex Induced by Mucosal Stimuli in Human and Guinea Pig Intestine,” Gastroenterology 111(5):1281-90, 1996; Wade, P. R., et al., “Localization and Function of a 5-HT Transporter in Crypt Epithelia of the Gastrointestinal Tract,” J. Neurosci. 16(7):2352-64, 1996).
The intestinal response to 5-HT has been best described in terms of the peristaltic reflex in in vitro models. Bulbring and Crema first showed that luminal 5-HT resulted in peristalsis (Bulbring et al., J. Physiol. 140:381-407, 1959; Bulbring et al., Brit. J. Pharm. 13:444-457, 1958). Since the stimulation of peristalsis by 5-HT was unaffected by extrinsic denervation (Bulbring et al., QJ Exp. Physiol. 43:26-37, 1958), the peristaltic reflex was considered to be intrinsic to the enteric nervous system. Using a modified Trendelenburg model that compartmentalized the peristaltic reflex into the sensory limb, the ascending contraction limb (orad to stimulus) and the descending relaxation limb (aborad to stimulus), Grider, et al. reported that (1) mucosal stimulation but not muscle stretch released 5-HT to activate a primary sensory neuron to release calcitonin gene-related peptide (CGRP) (Grider, et al., Am. J. Physiol 270:G778-G782, 1996) via 5-HT4 receptors in humans and rats (also 5-HT1p in rats) and 5-HT3 receptors in guinea pigs; (2) cholinergic interneurons are then stimulated by CGRP to initiate both ascending contraction via an excitatory motor neuron that depends on substances P and K and acetylcholine (Grider, et al., Am. J. Physiol. 257:G709-G714, 1989) and descending relaxation (Grider, Am. J. Physiol. 266:G1139-G1145, 1994; Grider, et al., 1996, Jin et al., J. Pharmacol. Exp. Ther. 288:93-97, 1999) via an inhibitory motor neuron that depends on pituitary adenylate cyclase-activating peptide (PACAP), nitric oxide and vasoactive inhibitory peptide (VIP) (Grider, et al., Neuroscience 54:521-526, 1993; Grider et al., J. Auton. Nerv. Syst. 50:151-159, 1994); and (3) peristalsis is controlled by [a] an opioid pathway that inhibits descending relaxation by suppressing the release of VIP; [b] a somatostatin pathway that inhibits this opioid pathway (Grider, Am. J. Physiol. 275:G973-G978 [1998]); and [c] a GABA (Grider, Am. J. Physiol. 267:G696-G701, 1994) and a gastrin releasing peptide (GRP) (Grider, Gastroenterol. 116:A1000, 1999) pathway that stimulate VIP release. An opioid pathway that inhibits the excitatory motor neurons responsible for ascending contraction has also been described (Gintzler, et al., Br. J. Pharmacol. 75:199-205, 1982; Yau, et al., Am. J. Physiol. 250:G60-G63, 1986). These observations are consistent with neuroanatomic and electrophysiological observations.
In addition, mucosal stroking has been found to induce 5-HT release by intestinal mucosal cells, which in turn activates a 5-HT4 receptor on enteric sensory neurons, evoking a neuronal reflex that stimulates chloride secretion (Kellum, J. M., et al., “Stroking Human Jejunal Mucosa Induces 5-HT Release and Cl− Secretion Via Afferent Neurons and 5-HT4 Receptors,” Am. J. Physiol. 277(3 Pt 1):G515-20, 1999).
Agonists of 5-HT4/5, 5-HT3 receptors, as well as opioid Δ receptor antagonists, were reported to facilitate peristaltic propulsive activity in the colon in response to mechanical stroking, which causes the endogenous release of 5-HT and calcitonin gene-related protein (CGRP) in the stroked mucosal area. (Steadman, C. J., et al., “Selective 5-Hydroxytrypamine Type 3 Receptor Antagonism With Ondansetron as Treatment for Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study,” Mayo Clin. Proc. 67(8):732-38, 1992). Colonic distension also results in CGRP secretion, which is associated with triggering the peristaltic reflex.
On the other hand, gastric distension is thought to be one of many factors inducing satiety and/or suppressing the rate of ingestion. (Bergstrom, J., “Mechanism of Uremic Suppression of Appetite,” J. Ren. Nutr. 9(3):129-32, 1999; Phillips, R. J. and T. L. Powley, “Gastric Volume Rather Than Nutrient Content Inhibits Food Intake,” Am. J. Physiol. 271(3 Pt 2):R766-69, 1996; Pappas, T. N., et al., “Gastric Distension is a Physiologic Satiety Signal in the Dog,” Dig. Dis. Sci. 34(10:1489-93, 1989; Lepionka, L., et al., “Proximal Gastric Distension Modifies Ingestion Rate in Pigs,” Reprod. Nutr. Dev. 37(4):449-57, 1997; McHugh, P. R. and T. H. Moran, “The Stomach, Cholecystokinin, and Satiety,” Fed. Proc. 45(5):1384-90, 1986; Lin, H. C., et al., “Frequency of Gastric Pacesetter Potential Depends on Volume and Site of Distension,” Am. J. Physiol. 270(3 Pt 1):G470-5, 1996c).
Another factor thought to contribute to satiety is glucagon-like peptide-1 (7-36) amide (GLP-1), which is processed from proglucagon in the distal ileum as well as in the central nervous system. In the periphery, GLP-1 acts as an incretin factor (inducer of insulin secretion) and profoundly inhibits upper gastrointestinal motility (e.g., ileal brake), the latter function presumably involving the central nervous system (Turton, M. D., et al., “A Role for Glucagon-Like Peptide-1 in the Central Regulation of Feeding,” Nature 379(6560):69-72, 1996; Dijk, G. and T. E. Thiele, “Glucagon-Like Peptide-1 (7-36) Amide: A Central Regulator of Satiety and Interoceptive Stress,” Neuropeptides 33(5):406-414, 1999). Within the central nervous system, GLP-1 has a satiating effect, since administration of GLP-1 into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-1 antagonists have the opposite effect (Dijk, G. and Thiele, 1999; but see, Asarian, L., et al., “Intracerebroventicular Glucagon-Like Peptide-1 (7-36) Amide Inhibits Sham Feeding in Rats Without Eliciting Satiety,” Physiol. Behav. 64(3):367-72, 1998). Lactate is another putative satiety factor. (Silberbauer, C. J., et al., “Prandial Lactate Infusion Inhibits Spontaneous Feeding in Rats,” Am. J. Physiol. Regul. Integr. Comp. Physiol. 278(3):R646-R653, 2000). Meyer taught a method for controlling appetite involving the delivery to the ileum of food grade nutrients, including sugars, free fatty acids, polypeptides, amino acids for controlling satiety (Meyer, J. H., Composition and Method for Inducing Satiety, U.S. Pat. No. 5,753,253).
Satiety can also be regulated by cytokines, such as IL-1, which is thought to operate directly on the hypothalamus or, alternatively, to increase the synthesis of tryptophan (Laviano, A., et al., “Peripherally Injected IL-1 Induces Anorexia and Increases Brain Tryptophan Concentrations,” Adv. Exp. Med. Biol. 467:105-08, 1999). Tryptophan is a precursor of 5-HT, which is itself a peripheral satiety signal, which has been thought to be acting through an afferent vagal nerve pathway. (E.g., Faris, P. L., et al., “Effect of Decreasing Afferent Vagal Activity With Ondansetron on Symptoms of Bulimia Nervosa: A Randomised, Double-Blind Trial,” Lancet 355(9206):792-97, 2000; Kitchener, S. J. and Dourish, C. T., “An Examination of the Behavioral Specificity of Hypophagia Induced by 5-HT1B, 5-HT1C and 5-HT2 Receptor Agonist Using the Post-Prandial Satiety Sequence in Rats, Psychopharmacology (Berl) 113(3-4):369-77, 1994; Simansky, K. J., et al., “Peripheral Serotonin is an Incomplete Signal for Eliciting Satiety in Sham-Feeding Rats,” Pharmacol. Biochem. Behav. 43(2):847-54, 1992; Edwards, S. and R. Stevens, “Peripherally Administered 5-Hydroxytryptamine Elicits the Full Behavioural Sequence of Satiety,” Physiol. Behav. 50(5):1075-77, 1991).
There may also be some interactions between 5-HT receptor-mediated effects and cholecystokinin-mediated effects on satiety. (Voight, J. P., et al., “Evidence for the Involvement of the 5-HT1A Receptor in CKK Induced Satiety in Rats,” Nauyn Schmiedebergs Arch. Pharmacol. 351(3):217-20, 1995; Varga, G., et al., “Effect of Deramciclane, a New 5-HT Receptor Antagonist, on Cholecystokinin-Induced Changes in Rat Gastrointestinal Function,” Eur. J. Pharmacol. 367(2-3):315-23, 1999; but see, Eberle-Wang, K. and K. J. Simansky, “The CKK-A Receptor Antagonist, Devazepide, Blocks the Anorectic Action of CKK but Not Peripheral Serotonin in Rats,” Pharmacol. Biochem. Behav. 43(3):943-47, 1992). The neuropeptide hormone cholecystokinin is known to induce satiety, inhibit gastric emptying, and to stimulate digestive pancreatic and gall bladder activity. (Blevins, J. E., et al., “Brain Regions Where Cholecystokinin Suppresses Feeding in Rats,” Brain Res. 860(1-2):1-10, 2000; Moran, T. H. and P. R. McHugh, “Cholecystokinin Suppresses Food Intake by Inhibiting Gastric Emptying,” Am. J. Physiol. 242(5):R491-97, 1982; McHugh, P. R. and T. H. Moran, 1986; Takahashi, H., et al., Composition for Digestion of Protein, JP5246846A).
Cholecystokinin, and other neuropeptides, such as bombesin, amylin, proopiomelanocortin, corticoptropin-releasing factor, galanin, melanin-concentrating hormone, neurotensin, agouti-related protein, leptin, and neuropeptide Y, are important in the endocrine regulation of energy homeostasis. (Maratos-Flier, E., Promotion of Eating Behavior, U.S. Pat. No. 5,849,708; Inui, A., “Feeding and Body-Weight Regulation by Hypthalamic Neuropeptides-Mediation of the Actions of Leptin,” Trends Neurosci. 22(2):62-67, 1999; Bushnik, T., et al., “Influence of Bombesin on Threshold for Feeding and Reward in the Rat,” Acta Neurobiol. Exp. (Warsz) 59(4):295-302, 1999; Sahu, A., “Evidence Suggesting That Galanin (GAL), Melanin-Concentrating Hormone (MCH), Neurotensin (NT), Proopiomelanocotin (POMC) and Neuropeptide Y (NPY) are Targets of Leptin Signaling in the Hypothalamus,” Endocrinol. 139(2):795-98, 1999). Many of these neuropeptides are multi-functional, binding several different receptors at different sites in the body. For example, neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is a potent appetite inducing signal molecule as well as a mitogen and a vasoconstrictor active in cardiovascular homeostatis. (Kokot, F. and R. Ficek, “Effects of Neuropeptide Y on Appetite,” Miner. Electrolyte Metab. 25(4-6):303-05, 1999).
Neuropeptide Y (NPY) and other neuropeptides may be involved in alternative biochemical satiety-regulating cascades within the hypothalamus. (E.g., King, P. J., et al., “Regulation of Neuropeptide Y Release From Hypothalamic Slices by Melanocortin-4 Agonists and Leptin,” Peptides 21(1):45-48, 2000; Hollopeter G., et al., “Response of Neuropeptide Y-Deficient Mice to Feeding Effectors,” Regul. Pept. 75-76:383-89, 1998). Bruno et al. taught a method of regulating appetite and metabolism in animals, including humans, which involves inter alia administering a composition that modulates synthesis and secretion of neuropeptide Y. (Bruno, J. F., et al., U.S. Pat. No. 6,013,622). Moreover, the neuropeptide Y-leptin endocrine axis has been considered a central mechanism of satiety regulation in mammals. Neuropeptide Y and leptin have opposite effects in the arcuate-paraventricular nucleus (ARC-PVN) of the hypothalamus, with leptin being satiety-inducing and a suppressor of neuropeptide Y (and agouti-related protein) expression. (E.g., Baskin, D. G., et al., “Leptin sensitive neurons in the hypothalamus,” Horm. Metab. Res. 31(5):345-50, 1999). In phenotypically obese mice with an ob/ob genotype, adipose cells fail to secrete leptin, and neuropeptide Y is overexpressed in the hypothalamus. (Erickson, J. C., et al., “Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y,” Science 274(5293):1704-07, 1996).
Neuropeptide Y mediates its effects through binding to Y1, Y2, Y4, and Y5 G-protein-coupled receptors on the surfaces of cells of the ARC-PVN of the hypothalamus. (Naveilhan, P., et al., “Normal Feeding Behavior, Body Weight and Leptin Response Require the Neuropeptide Y Y2 Receptor,” Nat. Med. 5(10):1188-93, 1999; King, P. J., et al., “Regulation of Neuropeptide Y Release by Neuropeptide Y Receptor Ligands and Calcium Channel Antagonists in Hypothalamic Slices,” J. Neurochem. 73(2):641-46, 1999). Peptide YY can also bind to these receptors. In addition, Y1, Y2, Y4/PP1, Y5 and Y5/PP2/Y2 receptors for peptide YY are localized in myenteric and submuscosal nerve cell bodies, endothelial cells, and endocrine-like cells of the rat intestinal tract. (Jackerott, M., et al., “Immunocytochemical Localization of the NPY/PYY Y1 Receptor in Enteric Neurons, Endothelial Cells, and Endocrine-Like Cells of the Rat Intestinal Tract,” J. Histochem Cytochem. 45(12):1643-50 (December 1997); Mannon, P. J., et al., “Peptide YY/neuropeptide Y Y1 Receptor Expression in the Epithelium and Mucosal Nerves of the Human Colon,” Regul. Pept. 83(1):11-19, 1999). But until now, a way of manipulating satiety has been unknown that exploits linkages between afferent and efferent neural pathways with the hypothalamic endocrine regulation of satiety and post-prandial visceral blood flow.
A treatment for visceral hyperalgesia or hypersensitivity is also a desideratum. Visceral hyperalgesia, or pain hypersensitivity, is a common clinical observation in small intestinal bacterial overgrowth (SIBO), Crohn's disease, and irritable bowel syndrome (IBS). As many as 60% of subjects with IBS have reduced sensory thresholds for rectal distension compared to normal subjects. (H. Mertz, et al., “Altered Rectal Perception is a Biological Marker of Patients With the Irritable Bowel Syndrome,” Gastroenterol. 109:40-52, 1995). While the experience of pain is intertwined with a person's emotions, memory, culture, and psychosocial situation (Drossman, D. A., and W. G. Thompson, “Irritable Bowel Syndrome: A Graduated, Multicomponent Treatment Approach,” Ann. Intern. Med. 116:1009-16, 1992) and the etiology for this hyperalgesia has remained elusive, evidence shows that certain cytokine mediated-immune responses can influence the perception of pain. Cytokines, including IL-1(α and β), IL-2, IL-6, and TNF-α, can be released in response to a variety of irritants and can modulate the perception of pain, possibly through the mediation of kinin B1 and/or B2 receptors (see, M. M. Campos, et al., “Expression of B1 kinin Receptors Mediating Paw Oedema Formalin-Induced Nociception. Modulation by Glucocorticoids,” Can. J. Physiol. Pharmacol. 73:812-19, 1995; de Campos, R. O. P., et al., “Systemic Treatment With Mycobacterium Bovis Bacillus Calmett-Guerin (BCG) Potentiates Kinin B1 Receptor Agonist-Induced Nociception and Oedema Formation in the Formalin Test in Mice,” Neuropeptides 32(5):393-403, 1998). Cytokine and neuropeptide levels are altered in IBS. An increase in substance P (neuropeptide)-sensitive nerve endings has been observed in subjects with IBS. (Pang, X., et al., “Mast Cell Substance P-Positive Nerve Involvement in a Patient With Both Irritable Bowel Syndrome and Interstitial Cystitis,” Urology 47:436-38, 1996). It has also been hypothesized that there is a sensitization of afferent pathways in IBS. (Mayer, E. A., et al., “Basic and Clinical Aspects of Visceral Hyperalgesia,” Gastroenterol 107:271-93, 1994; Bueno, L., et al., “Mediators and Pharmacology of Visceral Sensitivity: From Basic to Clinical Investigations,” Gastroenterol. 112:1714-43, 1997).
In summary, a need exists for manipulating upper gastrointestinal transit and post-prandial visceral blood flow, by which absorption of ingested nutrients and/or drugs in the small intestine can be optimized to prevent and/or reduce ineffectiveness thereof due to malabsorption and to enhance the bioavailability and effectiveness of drugs. A need also exists to manipulate satiety and to treat visceral hyperalgesia, by which optimal nutritional intake and visceral comfort can be achieved. Through a unifying conception of visceral neural regulatory pathways, the present invention satisfies these needs and provides related advantages as well.